Emesis Combo Quells CINV in Three Trials

Action Points

Note that multiple randomized trials support the addition of netupitant to more standard antiemetic agents for the treatment of chemotherapy-induced nausea and vomiting.

Be aware that the largest trial enrolled almost exclusively breast cancer patients.

A single-dose antiemetic regimen provided superior control of chemotherapy-induced nausea and vomiting (CINV) as compared with a standard multidose regimen, according to results of three randomized trials.

In each trial, the fixed-dose combination of netupitant and palonosetron (Aloxi) led to a significantly higher rate of complete response during the delayed phase of the first cycle of chemotherapy versus control regimens. Complete response rates with netupitant-palonosetron (NEPA) regimen ranged from 76% to 89%, representing absolute differences of 5% to 14% versus the control groups.

Taken together, results of the three trials suggest a "winning team" in the search for optimal management of CINV, reported Matti Aapro, MD, of the Multidisciplinary Oncology Institute in Genolier, Switzerland, and colleagues in the July issue of Annals of Oncology.

"If the present registration trial results are replicated in the 'real' clinical world, then the NEPA formulation appears to be an advance in terms of overall efficacy and simplicity of dosing regime with the maintenance of efficacy over multiple cycles of chemotherapy being particularly encouraging," Paul L.R. Andrews, PhD, of St George's University of London, said in an accompanying editorial.

CINV has a complex pathophysiology that involves multiple neurotransmitters and receptors. Recognition of the complexity has led to guideline recommendations supporting co-administration of agents that target different molecular pathways to prevent CINV.

Clinical research and guidelines support prophylaxis with a 5-HT3 receptor antagonist and dexamethasone for patients receiving moderately emetogenic chemotherapy. For protection against the effects of highly emetogenic chemotherapy regimens, the combination of a 5-HT3 receptor antagonist, dexamethasone, and a neurokinin-1 (NK1) receptor antagonist are recommended, Aapro's group noted in their introduction to results of the largest of the three trials.

Moderately emetogenic chemotherapy includes widely used anthracycline-cyclophosphamide combinations. However, many patients treated with the combination have risk factors that place them at higher risk for CINV, such as young age and female sex. Studies have shown that adding an NK1 receptor antagonist to the 5-HT3 receptor antagonist-dexamethasone regimen is beneficial, and clinical guidelines have recommended that selected higher-risk patients receive three-drug prophylaxis for CINV.

NEPA is a fixed-dose combination of an NK1 receptor antagonist (netupitant) and a 5-HT3 receptor antagonist (palonosetron). Pharmacokinetic and pharmacodynamic studies have shown that palonosetron achieves long-lasting receptor inhibition and inhibits communication between 5-HT3 and NK1 receptors, the authors continued. Moreover, the combination of palonosetron and netupitant has been shown to produce enhanced inhibition of the substance P response as compared with either agent alone.

Aapro and colleagues reported data from a multinational randomized trial involving 1,455 cancer patients with no prior chemotherapy. More than 97% of the patients had breast cancer, and, in all cases, patients received anthracycline-cyclophosphamide combination chemotherapy.

The patients were randomized a single dose of NEPA versus a single dose of palonosetron. All patients received dexamethasone on day one. The primary endpoint was complete response, defined as no emesis or rescue medication during the delayed phase (25 to 120 hours) of the first cycle of chemotherapy.

The authors reported that 76.9% of the NEPA group and 69.5% of the control group met the primary endpoint (P=0.001). NEPA also demonstrated superiority for the primary endpoint during the acute phase (first 24 hours: 88.4% versus 85.0%, P=0.047) and overall (0 to 120 hours: 74.3% versus 66.6%, P=0.001).

The NEPA group fared significantly better with respect to the secondary endpoint of no emesis, no significant nausea, and complete protection. With the exception of no significant nausea and complete protection during the acute phase, NEPA demonstrated statistically significant advantages over the control regimen at all time points (P=0.025 to P<0.001).

The experimental group also had significantly higher scores on an assessment of the impact of nausea and vomiting on activities of daily living, including the nausea domain, vomiting domain, and combined score.

The NEPA group had a higher incidence of adverse events (76% versus 69.9%), but serious adverse events, treatment-related adverse events, and discontinuation because of adverse events occurred at similar rates in the two groups.

Exploratory Arm

Investigators in another multinational trial, published in a separate paper in the Annals of Oncology, evaluated three different doses of netupitant (100, 200, and 300 mg) in the NEPA regimen for prevention of nausea and vomiting in patients treated with highly emetogenic chemotherapy. None of the patients had prior exposure to chemotherapy, and all of them received cisplatin-based regimens for various types of solid tumors, reported Paul Hesketh, MD, of Lahey Hospital and Medical Center in Burlington, Mass., and colleagues.

Data analysis included 694 patients, who were randomized to the three NEPA groups, a single dose of palonosetron as the control, or an exploratory regimen consisting of aprepitant (Emend) plus intravenous ondansetron for 3 days. All patients received dexamethasone on days one through four. The primary endpoint was complete response during the overall phase (0 to 120 hours).

All three NEPA groups demonstrated superiority over the control regimen. The highest netupitant dose resulted in the highest response rate (89.6% versus 76.5% for control, P<0.004). The netupitant 100 and 200 mg groups had complete response rates of 87.4% and 87.6%, respectively (P=0.018 and P=0.017 versus control).

The exploratory regimen led to a higher response rate (86.6%, P≤0.05) and had a higher proportion of patients with no emesis (87.3%, P≤0.05) compared with the palonosetron control group.

Adverse event rates were similar across the five treatment groups, and events were mild or moderate in 95% of cases.

Multicycle Evaluation

The third trial extended the evaluation period across multiple cycles of chemotherapy. Previously untreated cancer patients were randomized 3:1 to a single dose of NEPA plus dexamethasone on day one or to a control regimen consisting of aprepitant plus palonosetron plus dexamethasone for 3 days. As in the other two trials, the primary endpoint was complete response.

The final analysis included 413 patients, who completed a combined total of 1,961 cycles of chemotherapy. Three-fourths of the cycles involved moderately emetogenic chemotherapy, and the remainder involved highly emetogenic chemotherapeutic regimens, Richard Gralla, MD, of Albert Einstein College of Medicine in New York City, and colleagues reported in the Annals of Oncology.

The primary analysis was complete response during the first cycle of chemotherapy. In the NEPA group, 81% of patients achieved complete responses from 0 to 120 hours versus 76% in the control group. The NEPA group maintained the advantage over the control group through five cycles of chemotherapy, as the absolute between-group difference ranged from 2% to 6%. Complete response rates in subsequent cycles ranged from 86% to 92% in the NEPA group and from 81% to 88% in the control group.

During the first cycle of therapy, treatment-emergent adverse events occurred in 64.6% of the NEPA group and 61.5% of the control group. Over the entire multicycle study period, adverse event rates were 86.0% with NEPA and 91.3% with the control regimen. Treatment-related adverse events were uncommon, occurring in 5.2% and 2.9% of the NEPA and control groups during the first cycle and in 10.1% versus 5.8% across multiple cycles of therapy.

Gralla and colleagues reported that 16 deaths in the NEPA group, including seven during the first cycle. One death occurred in the control group. All of the deaths were considered unrelated to study medications.

All three studies were supported by Helsinn Healthcare, and Helsinn employees are among the authors.

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